Facultad de Ciencias Químicas, Universidad Autónoma de Nuevo León, Av. Universidad S/N, Ciudad Universitaria, San Nicolás de los Garza, NL 66451, Mexico.
Laboratorio de Diseño Asistido por Computadora y Síntesis de Fármacos, Facultad de Quimica, Universidad Autónoma de Querétaro, Centro Universitario, Cerro de las Campanas S/N, Santiago de Querétaro, QT 76010, Mexico.
Molecules. 2021 Feb 19;26(4):1096. doi: 10.3390/molecules26041096.
Preliminary bioassay-guided fractionation was performed to identify cytotoxic compounds from , a plant that is used in Mexican ethnomedicine. Organic and aqueous extracts were prepared from 's leaves and evaluated against two cancer cell lines. The CHCl/MeOH (1:1) active extract was fractionated, and the resulting fractions were assayed against prostate adenocarcinoma PC3 and breast adenocarcinoma MCF7 cell lines. Active fraction was further analyzed by high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry analysis to identify its active constituents. Among the compounds that were responsible for the cytotoxic effects of this fraction were flavonoids, phenolic acids, and aromatic compounds, of which -coumaric acid (-CA) and its derivatives were abundant. To understand the mechanisms that underlie -CA cytotoxicity, a microarray assay was performed on PC3 cells that were treated or not with this compound. The results showed that mitogen-activated protein kinases (MAPKs) that regulate many cancer-related pathways were targeted by -CA, which could be related to the reported effects of reactive oxygen species (ROS). A molecular docking study of -CA showed that this phenolic acid targeted these protein active sites (MAPK8 and Serine/Threonine protein kinase 3) at the same binding site as their inhibitors. Thus, we hypothesize that -CA produces ROS, directly affects the MAPK signaling pathway, and consequently causes apoptosis, among other effects. Additionally, -CA could be used as a platform for the design of new MAPK inhibitors and re-sensitizing agents for resistant cancers.
初步的生物测定指导分离用于鉴定来自墨西哥传统医学中使用的植物 的细胞毒性化合物。从 ' 的叶子中提取有机和水提取物，并针对两种癌细胞系进行评估。CHCl/MeOH（1:1）活性提取物进行了分离，所得馏分针对前列腺腺癌 PC3 和乳腺腺癌 MCF7 细胞系进行了测定。活性馏分通过高效液相色谱-四极杆飞行时间质谱分析进一步分析，以鉴定其活性成分。负责该馏分细胞毒性作用的化合物包括黄酮类、酚酸类和芳香族化合物，其中 - 肉桂酸（-CA）及其衍生物含量丰富。为了了解 -CA 细胞毒性的机制，对用或不用该化合物处理的 PC3 细胞进行了微阵列分析。结果表明，调节许多与癌症相关途径的丝裂原激活蛋白激酶（MAPKs）是 -CA 的靶点，这可能与报道的活性氧（ROS）的作用有关。-CA 的分子对接研究表明，这种酚酸靶向这些蛋白质活性位点（MAPK8 和丝氨酸/苏氨酸蛋白激酶 3），与它们的抑制剂在相同的结合位点。因此，我们假设 -CA 产生 ROS，直接影响 MAPK 信号通路，从而导致细胞凋亡等作用。此外，-CA 可以用作设计新的 MAPK 抑制剂和重新敏化耐药性癌症的平台。
